Malaria, the most common parasitic disease of humans, remains a major health and economic burden in most tropical countries. Large areas of Central and South America, Hispaniola (Haiti and the Dominican Republic), Africa, the Middle East, the Indian subcontinent, Southeast Asia, and Oceania are considered as malaria-risk areas. It leads to a heavy toll of illness and death especially amongst children and pregnant women. According to the World Health Organization, it is estimated that the disease infects about 400 million people each year, and around two to three million people die from malaria every year. There are four kinds of malaria parasites that infect human: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae. 
Malaria spreads from one person to another by the bite of mosquito, Anopheles gambiae which serves as vector. When a mosquito sucks the blood of human, sporozoites are transfused into the human body together with saliva of the mosquito. The sporozoites enter into the hepatocytes, reproduce asexually and finally enter into the blood stream. The parasites continue to multiply inside the red blood cells, until they burst and release large number of merozoites. This process continues, destroying a significant number of blood cells and causing the characteristic paroxysm (“chills and fever”) associated with the disease. In the red blood cells, some of the merozoites become male or female gametocytes. These gametocytes are ingested by the mosquito when it feeds on blood. The gametocytes fuse in the vector's gut; sporozoites are produced and are migrated to the vector's salivary glands.
The clinical symptoms of malaria are generally associated with the bursting of red blood cells causing an intense fever associated with chills that can leave the infected individual exhausted and bedridden. More severe symptoms associated with repeat infections and/or infection by Plasmodium falciparum include anaemia, severe headaches, convulsions, delirium and, in some instances, death.
Quinine, an antimalarial compound that is extracted from the bark of cinchona tree, is one of the oldest and most effective drugs in existence. Chloroquine and mefloquine are the synthetic analogs of quinine developed in 1940's, which due to their effectiveness, ease of manufacture, and general lack of side effects, became the drugs of choice. The downside to quinine and its derivatives is that they are short-acting and have bitter taste. Further, they fail to prevent disease relapses and are also associated with side effects commonly known as “Chinchonism syndrome” characterized by nausea, vomiting, dizziness, vertigo and deafness. However, in recent years, with the emergence of drug-resistant strains of parasite and insecticide-resistant strains of vector, the treatment and/or control of malaria is becoming difficult with these conventional drugs.
Malarial treatment further progressed with the discovery of Artemisinin (qinghaosu), a naturally occurring endoperoxide sesquiterpene lactone isolated from the plant Artemisia annua (Meshnick, S. R. et al., Microbiol. Rev., 60, 301-315 (1996); Vroman J. A. et al., Curr. Pharm. Design, 5, 101-138 (1999); Dhingra V. K. et al., 66, 279-300 (2000)), and a number of its precursors, metabolites and semi synthetic derivatives which have shown to possess antimalarial properties. The antimalarial action of artemisinin is due to its reaction with iron in free heme molecules of the malaria parasite, with the generation of free radicals leading to cellular destruction. This initiated a substantial effort to elucidate its molecular mechanism of action (Jefford, C., dv. Drug Res., 29, 271-325 (1997); Cumming, J. N. et al., Adv. Pharmacol., 37, 254-297 (1997)) and to identify novel antimalarial peroxides (Dong, Y. and Vennerstrom, J. L., Expert Opin. Ther. Patents, 11, 1753-1760 (2001)).
Although the clinically useful semi synthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have several disadvantages including recrudescence, neurotoxicity, (Wesche, D. L. et al., Antimicrob. Agents. Chemother., 38, 1813-1819 (1994)) and metabolic instability (White, N. J., Trans. R. Soc. Trop. Med. Hyg., 88, 41-43 (1994)). A fair number of these compounds are quite active in vitro, but most suffer from low oral activity (White, N. J., Trans. R. Soc. Trop. Med. Hyg., 88, 41-43 (1994) and van Agtmael et al., Trends Pharmacol. Sci., 20, 199-205 (1999)).
Thus there exists a need in the art to identify new peroxide antimalarial agents, especially those which are easily synthesized, are devoid of neurotoxicity, and which possess improved solubility, stability and pharmacokinetic properties. Following that, many synthetic antimalarial 1,2,4-trioxanes (Jefford, C., Adv. Drug Res, 29, 271-325 (1997); Cumming, J. N. et al., Adv. Pharmacol., 37, 254-297 (1997)), 1,2,4,5-tetraoxanes (Vennerstrom, J. L. et al., J. Med. Chem., 43, 2753-2758 (2000)), and other endoperoxides have been prepared. Various patents/applications disclose means and method for treating malaria using Spiro or dispiro 1,2,4-trioxolanes for example, in U.S. Patent Application No. 2004/0186168 and U.S. Pat. Nos. 6,486,199 and 6,825,230. The present invention relates to solid dosage forms of the various Spiro or dispiro 1,2,4-trioxolanes antimalarial compounds disclosed in these patents/applications and are incorporated herein by reference.
Active compounds representing various Spiro and dispiro 1,2,4-trioxolane derivatives possess excellent potency, efficacy against Plasmodium parasites, and a lower degree of neurotoxicity, in addition to their structural simplicity and ease of synthesis. Furthermore, these compounds have half lives which are believed to permit short-term treatment regimens comparing favorably to other artemisinin-like drugs. In general, the therapeutic dose of trioxolane derivative may range between about 0.1-1000 mg/kg/day, in particular between about 1-100 mg/kg/day. The foregoing dose may be administered as a single dose or may be divided into multiple doses. For malaria prevention, a typical dosing schedule could be, for example, 2.0-1000 mg/kg weekly beginning 1-2 weeks prior to malaria exposure continued up to 1-2 weeks post-exposure.
However, in spite of many advantages of trioxolanes, there are certain limitations for formulators developing formulations with trioxolones, the first being their susceptibility to degradation in presence of moisture that results in reduced shelf lives. Another is their bitter taste, which can result in poor compliance of the regimen or selection of another, possibly less effective, therapeutic agent.
We have now discovered that a stable antimalarial oral solid dosage form comprising Spiro or dispiro 1,2,4-trioxolanes can be prepared by controlling the water content below a certain critical limit. Further, the bitter taste can be masked by applying a film coating layer to the solid dosage form.